Side Effects Data, Too, Impress for New Prostate Cancer Drugs

By Anette BreindlScience Editor

Only two weeks after disappointing news on its Alzheimer's disease candidate, Dimebon (latrepirdine), Medivation Inc. had better news to share. Data from its Phase III AFFIRM trial of prostate cancer drug MDV3100, which will be presented later this week, were highlighted in a press conference put on by the American Society of Clinical Oncology 2012 Genitourinary Cancers Symposium Tuesday.

Also presented were Phase III data from the ALSYMPCA trial of Algeta ASA's Alpharadin (radium-223 chloride).

Top-line data for both trials had already been presented. In fact, both trials were stopped early because interim analyses had shown strong efficacy. And so their survival benefits were no surprise. The AFFIRM trial, which looked at 1,199 men with prostate cancer that had progressed after treatment with hormone therapy and docetaxel, extended survival by an average of 4.8 months, to 18.4 months, on MDV3100 treatment. Alpharadin's survival benefit in the ALSYMPCA trial, which looked at 922 castration-resistant prostate cancer patients with symptomatic bone metastases, was 2.8 months (See BioWorld Today, Nov. 4, 2011, and June 7, 2011.)

But the details of the safety data, too, were impressive for both drugs.

Serious adverse events were no higher overall for treated patients than for the control group in Medivation's AFFIRM trial. In fact, the absolute numbers of high-grade adverse events were lower in the treated group, though the numbers were not different enough to translate into statistical significance. (Lower-grade adverse events did occur more frequently in the treated group, but those were generally too mild to necessitate lowering the dose.)

And Algeta's Alpharadin did have one side effect that was significantly lower in treated patients: bone pain. Those data are perhaps not highly surprising, given that Alpharadin is a radiation agent that is specifically targeted toward bone metastases.

Early stage trials had shown some risk of seizures with MDV3100. Those seizures were seen at higher doses than the 160 mg used in the AFFIRM trial. Five out of 800 patients treated with MDV3100 in the AFFIRM trial did have seizures, while none of the control patients did.

Principal investigator Howard Scher of Memorial Sloan-Kettering Cancer Center gave an example of how well tolerated MDV3100 is overall, and how effective it can be, by pointing out that "I had the privilege of treating the first patient on this drug, in July of 2007. And that patient is still on it."

Side effects for Alpharadin, too, were mostly no different in treated and control groups. For Alpharadin, which homes to the bone marrow and specifically targets bone metastases, the biggest concern would be secondary leukemias or bone marrow failure. But principal investigator Oliver Sartor, who is at Tulane University School of Medicine, said his team had observed no such events – possibly because Alpharadin is such a targeted therapy.

The drug "localizes to the stroma directly adjacent to the tumor," he told reporters at the press conference. "It ends up irradiating the tumor and the stroma, but it does so within an extremely localized fashion... it is like a little bomb going off" near the tumor. "But it doesn't affect the surrounding tissue much at all."

Both principal investigators, while stressing that they could not speak for regulatory agencies, were sanguine about the drugs' chances for approval. Algeta and partner Leverkusen, Germany-based Bayer AG plan to file for Alpharadin approval by mid-2012, once their manufacturing facility is ready for vetting. Sartor said, "I've seen a lot of drugs come through the pipeline," and that Alpharadin "should be very well received."

"That's a personal opinion, of course – I can't speak for the regulatory agencies," he added. But Alpharadin, if it is approved, "may provide a new standard of care for the treatment of castrate-resistant prostate cancer patients with bone metastases."

Scher, too, noted that "I'm not the FDA. But when you see this kind of survival benefit and side effect profile . . . I would say that [MDV3100] should be approved relatively quickly."

Medivation and its partner Astellas Pharma Inc., of Tokyo, plan to hold a pre-new drug application meeting with the FDA early this year, and plan to update their timeline for regulatory filing after that meeting.

If both drugs are approved, press conference moderator Nicholas Vogelzang said they are "definitely going to change the way we take care of patients every day in the office." Vogelzang is chair and medical director of the Developmental Therapeutics Committee of U.S. Oncology.

Both drugs extend lifespan through quite different mechanisms, and so they could be used sequentially – or possibly even as combination therapy.

Ultimately, the two drugs "will probably be combined," Sartor said. And "in combination, [they] may add even more value than what we see today."